Mini-Review

Modulation of inflammation by -27 Markus Bosmann* and Peter A. Ward†,1 *Center of Thrombosis and Hemostasis and Department of Hematology and Oncology, University Medical Center, Mainz, Germany; and †Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA RECEIVED FEBRUARY 27, 2013; REVISED JUNE 14, 2013; ACCEPTED JULY 9, 2013. DOI: 10.1189/jlb.0213107

ABSTRACT lyze structure, signaling, and biological effects of IL-27. De- A growing body of evidence suggests an essential role spite accumulating literature on IL-27, several aspects of this of the heterodimeric , IL-27, for regulating im- cytokine remain enigmatic. In this review, we will provide a munity. IL-27 is composed of two subunits (p28 and perspective of the current knowledge of IL-27 functions and EBI3) and is classified as a member of the IL-12 family implications during autoimmune and infectious diseases. We of . APCs have been recognized as a major present C5a as a selective regulator of IL-27 gene expression. cellular source of IL-27 following activation with micro- bial products or IFNs (types I and II). In this review, we Furthermore, we dissect the available literature, classifying describe the current knowledge of the implications of IL-27 as a proinflammatory or anti-inflammatory factor during IL-27 during the pathogenesis of infectious and autoim- acute and chronic models of inflammation. mune diseases. Experimental studies have used genet- ically targeted IL-27RAϪ/Ϫ mice, EBI3Ϫ/Ϫ mice, and p28Ϫ/Ϫ mice or involved study designs with administra- tion of bioengineered IL-27/IL-27RA homologs. STRUCTURE OF IL-27 Whereas many reports have described that IL-27 sup- presses inflammation, we also review the current litera- The heterodimeric, glycosylated IL-27 is assembled by ture, suggesting promotion of inflammation by IL-27 in the subunits p28 (also known as IL-27p28, IL-27A, IL-30) and some settings. Recent advances have also been made EBI3 [1]. EBI3 is a 229-aa protein (mouse: 228 aa) encoded in understanding the cross-talk of cleavage products of on human 19 (mouse: chromosome 17). The the complement system with IL-27-mediated immune subunit p28 consists of 243 aa (mouse: 234 aa) and is located responses. Additional data on IL-27 have been ob- on human chromosome 16 (mouse: chromosome 7). Whereas tained recently by observational studies in human pa- the predicted structure of p28 is a four-helical cytokine, EBI3 tients with acute and chronic inflammatory diseases. Collectively, the findings from the past decade identify is considered to be a soluble receptor [2]. The predicted in- IL-27 as a critical immunoregulatory cytokine, espe- terface of p28/EBI3 is composed of noncovalent bonds of dis- cially for T cells, whereas some controversy is fueled by tinct hydrophobic and polar properties involving specific results challenging the view of IL-27 as a classical si- residues of p28 (Trp97) and EBI3 (Phe97, Asp210, lencer of inflammation. J. Leukoc. Biol. 94: 1159–1165; Glu159) [2]. IL-27 displays with members 2013. of the IL-6/IL-12 family of cytokines. Genes encoding for ho- mologs of IL-27 subunits have been identified in nearly 20 mammalian species, whereas little information is available for other vertebrates. IL-27 was first described by Pflanz and colleagues [1] in 2002 In humans and rodents, other binding partners for p28 or as a cytokine with activity on T cells. Notably, the discovery of EBI3 exist (Fig. 1). EBI3 can associate with the subunit p35 IL-27 may have been complicated by the fact that the different (IL-12A), resulting in the cytokine IL-35 [3]. In addition, p28 protein chains of IL-27 are encoded on independent gene loci. Over the past decade, scientific efforts have aimed to ana- appears to have another binding partner, CLF-1 [4]. The exis- tence and biological relevance of homodimers (EBI3/EBI3; p28/p28) and isolated secreted subunits of p28 or EBI3 are not entirely clear, but such molecules may act as natural antag- Abbreviations: Ϫ/Ϫϭdeficient, AhRϭaryl hydrocarbon receptor, C3a/C4a/ onists of heterodimeric IL-27 [5]. C5aϭcomplement component C3a/C4a/C5a, CLF-1ϭcytokine-like factor 1, EAEϭexperimental autoimmune encephalomyelitis, EBI3ϭEBV-induced gene 3, Egr-2ϭearly growth response gene 2, Foxp3ϭforkhead box p3, H1N1ϭinfluenza A, HSVϭHerpes simplex virus, IRFϭIFN regulatory factor, p28ϭIL-27 subunit p28, IL-30, SNPϭsingle nucleotide polymorphism, ϭ ϭ TNBS 2,4,6-trinitrobenzene sulfonic acid, Tr1 type 1 regulatory , 1. Correspondence: Dept. of Pathology, University of Michigan Medical Tregϭregulatory T cell, TRIFϭToll/IL-1R domain-containing adapter-induc- School, 1301 Catherine Rd., Ann Arbor, MI 48109-5602, USA. E-mail: ing IFN-␤ [email protected]

0741-5400/13/0094-1159 © Society for Leukocyte Biology Volume 94, December 2013 Journal of Leukocyte Biology 1159 and II IFNs [23–25]. IFNs may also be a relevant trigger to initi- ate IL-27 production during autoimmune diseases. Another pathway to activate IL-27 production in myeloid cells is activation of the costimulatory molecule, 4-1BB (CD137), a member of the TNFR family, using agonistic anti- bodies [26]. Figure 1. Subunits of IL-12 family members and their known associa- Extracellular ATP, which is viewed as a “danger signal” fol- tions as heterodimers. p35, IL-12A; p40, IL-12B. lowing tissue injury, mediates suppression of p28 and less po- tently of EBI3 [27]. These effects involve signaling via puriner-

gic (P2) receptors (e.g., P2Y11 receptor) [27]. In addition, IL-27R AND SIGNALING IL-27 appears to be silenced following activation of the com- plement system. IL-27 binds to a heterodimeric receptor complex, which is composed of a -binding chain, IL-27RA (WSX-1, TCCR), and an additional signal-transducing chain, gp130 [6, 7]. Of IL-27 AND THE COMPLEMENT SYSTEM note, IL-27RA includes a cytoplasmatic domain with Box 1 mo- The complement system is part of innate immune defenses tif binding sites for JAK1/2, which contributes to signal trans- and is required for immediate clearance of pathogens [28, duction of the IL-27RA/gp130 dimer [6]. The common gp130 29]. In addition, complement activation products, such as C3a, chain is shared by several other receptors for signaling of cyto- C4a, and C5a, act as potent anaphylatoxins to orchestrate the kines, such as IL-6, IL-11, and leukemia inhibitory factor [8]. activation and chemotaxis of various immune cells [29]. Com- The situation becomes even more complex with heterodimers plement cleavage products induce complex signaling cascades of CLF-1/p28 binding to a trimeric receptor complex com- to maintain immune surveillance and tissue homeostasis [28]. posed of IL-27RA/gp130/IL-6RA [9]. For instance, the classical receptor for C5a (C5aR) is ex- Whereas gp130 is found widely in various tissues, the expres- pressed abundantly on PMN leukocytes and to a lesser extent, sion of IL-27RA appears to be more restricted to immune on macrophages [15]. Ligation of C5a with C5aR suppresses cells, such as T, B, NK, plasma, and possibly cells of the my- gene expression and release of p28 from F4/80ϩ macrophages eloid lineage [7, 10, 11]. However, IL-27RA may also be ex- [15, 30, 31]. Likewise, the C5a degradation product, C5adesArg, pressed on transformed, malignant, nonimmune cells [12]. has retained some functionality to antagonize p28 production IL-27, via IL-27RA/gp130, activates JAK and STAT1/STAT3. from macrophages, presumably with less potency than C5a STAT1 and STAT3 modulate the activity of downstream T cell [15]. During endotoxic shock, higher amounts of p28 are gen- lineage-specific transcription factors, such as T-bet (Th1), erated in C5aRϪ/Ϫ mice compared with WT mice, whereas GATA-3 (Th2), and retinoic acid receptor-related orphan re- no such effects have been observed in mice deficient in the ␥ ceptor t (Th17). In addition, IL-27 signaling activates p38 second , C5L2 [15]. In cell culture experiments, MAPK and recruits the transcription factors c-Maf and the lower frequencies of F4/80ϩp28ϩ macrophages were ob- AhR [13, 14]. served, when LPS (TLR4 activation) was combined with C5a treatment. The inhibitory effects of C5a on p28 gene expres- REGULATION OF IL-27 GENE EXPRESSION BY MICROBIAL PRODUCTS AND ENDOGENOUS FACTORS IL-27 is expressed mainly by APCs (macrophages and DCs) after encountering microbial products. Abundant quantities of IL-27 are secreted after activation of PRRs, such as TLR3 (polyinosinic:polycytidylic acid), TLR4 (LPS), and in some re- ports, TLR7 (loxoribine) and TLR9 (CpG) [15–17]. Irradiated gram-negative bacteria (e.g., Escherichia coli) induced expres- sion of p28 in human monocyte-derived DCs [18]. Similar re- sults were obtained for IL-27 induction by viable Salmonella enteritidis [19]. Production of IL-27 has been noted during vi- ral, bacterial, protozoan, and fungal infections in vivo [17, 20– 22] (Fig. 2). TLRs recruit the adaptor molecules MyD88 and TRIF for initia- tion of downstream signaling cascades. After activation of TLR4 with LPS, MyD88 and TRIF are required for full activation of Figure 2. Regulation of IL-27 p28 gene expression by the complement system in the context of infection. Viral infections activate the TLR3 IL-27 gene expression [23, 24]. Subsequently, transcription fac- ␬ pathway, whereas bacterial infections predominantly activate the TLR4 tors, such as NF- B (c-Rel), IRF-1, IRF-3, and IRF-9, bind to the pathway. Simultaneous, complement activation results in generation of promoter region of p28 [23–25]. An important amplifying circuit the anaphylatoxin, C5a, which recruits PI3K-Akt for selective inhibition for IL-27 production has been identified as endogenous types I of the TLR4 pathway to limit IL-27 production.

1160 Journal of Leukocyte Biology Volume 94, December 2013 www.jleukbio.org Bosmann and Ward IL-27 regulates inflammation sion are linked to activation of PI3K/Akt signaling by C5a activating geneϪ/Ϫ recipient mice, but on the other side, [15]. An in vivo blockade of Akt, using the small molecule in- IL-27 was indispensable for prevention of colitis by Tregs [41]. hibitor, wortmannin, resulted in threefold higher plasma con- Apparently, IL-27 confers long-term survival of T cells by centrations of p28 during endotoxic shock [15]. Interestingly, down-regulation of and up-regulation of antiapop- suppression of IL-27 by C5a was specific when IL-27 was in- totic caspase 8 homologue Fas-associated death domain-like duced via TLR4, whereas TLR3-induced IL-27 was unaffected IL-1␤-converting enzyme-like inhibitory protein [41]. [15]. This demonstrates that the IL-27 appearance may be spe- IL-27 was essential for production of IL-21 by Th follicular cifically regulated by C5a, depending on the context of bacte- cells, via STAT3, in germinal centers [42]. In IL-27RAϪ/Ϫ rial (TLR4) as opposed to viral (TLR3) infections (Fig. 2). In mice, the production of high-affinity /autoantibod- the future, it may be important to evaluate to what extent ies was reduced, resulting in diminished severity of glomerulo- complement-driven regulation of IL-27-dependent immune nephritis [42]. In proteoglycan-induced arthritis, IL-27RAϪ/Ϫ responses participates in development and progression of mice were protected, including delayed onset and reduced chronic diseases and inflammatory clinical conditions. severity of disease, as documented by less cartilage destruction compared with WT mice [35]. The diminished arthritis in IL- 27RAϪ/Ϫ mice was associated with fewer IFN-␥-producing T ACTIVATION OF INFLAMMATION BY cells and Th17 cells [35]. On the other hand, the implications IL-27 of IL-27 in arthritis are puzzling, given other reports that ad- In first reports, IL-27 was described as promoting a rapid, ministration of bioengineered EBI3-L-p28-Fc fusion protein clonal expansion of naive CD4ϩ T cells and triggering IFN-␥ ameliorated joint inflammation in collagen-induced arthritis production by CD4ϩ T cells [1]. Since then, many investiga- (ref. [36]; also reviewed elsewhere in ref. [43]). EBI3Ϫ/Ϫ tions into the role of IL-27 in diseases have used IL-27RAϪ/Ϫ mice were protected from Con A-induced T cell-dependent mice (disruption of IL-27 signaling; Table 1). In a T cell-trans- hepatitis, a disease model associated with IFN-␥ production, fer model of colitis, IL-27RAϪ/Ϫ mice were protected from along with pSTAT1 and T-bet activation [44]. STAT1 was re- colonic inflammation and weight loss [40]. Such mice showed ported to mediate IL-27-induced NO production from perito- reduced frequencies of Foxp3ϩ Tregs and reduced IFN-␥ pro- neal-elicited macrophages [45]. duction [40]. In another study, CD4ϩCD45RBϩ T cells from It has been reported that in lung fibroblasts, IL-27 induces IL-27RAϪ/Ϫ mice failed to induce colitis in recombination- the expression of CXCL10 (IFN-␥-inducible protein 10) via

Table 1. Effects of IL-27 in Experimental Models of Disease

Disease model IL-27 strategy Major findings Ref. EAE IL-27RAϪ/Ϫ IL-27 suppressed development of Th17 cells. [32] Toxoplasma gondii infection IL-27RAϪ/Ϫ IL-27 antagonized Th17 cell functions during [33] neuroinflammation. T. gondii infection IL-27RAϪ/Ϫ Absence of IL-27 mediates lethal T cell-mediated [21] inflammatory disease; excessive production of IFN-␥. T. gondii infection IL-27RAϪ/Ϫ IL-27 induced IL-10 in T cells via STAT3. [34] Proteoglycan-induced arthritis IL-27RAϪ/Ϫ IL-27 promoted severity of arthritis; induction of [35] Th1 response. Collagen-induced arthritis EBI3-L-p28-Fc IL-27 attenuated histology scores and joint [36] inflammation; less proinflammatory cytokines. Listeria monocytogenes IL-27RAϪ/Ϫ IL-27 promoted IL-10 production; lower frequency [37] of IL-10ϩ T cells in IL-27RAϪ/Ϫ mice. Trypanosoma cruzi infection IL-27RAϪ/Ϫ IL-27 antagonized parasitemia, severe injury, [38] mortality, and proinflammatory cytokines (IL-6, TNF-␣, IFN-␥). Septic peritonitis IL-27RA-Fc soluble receptor There was an improved survival with blockade of [20] IL-27 during sepsis. TNBS-induced colitis Single-chain human IL-27 IL-27 treatment improved disease scores and [39] inflammation in colon and LNs; proinflammatory cytokines (IL-17) were suppressed. T cell-dependent colitis IL-27RAϪ/Ϫ IL-27RAϪ/Ϫ showed less weight loss and colonic [40] inflammation, including IFN-␥ production; more Foxp3ϩ T cells. N.A. p28-Transgenic mice There was overexpression of p28 (in T and B [5] cells), independent of EBI3; p28 antagonized interaction of IL-6 with gp130.

www.jleukbio.org Volume 94, December 2013 Journal of Leukocyte Biology 1161 p38 MAPK and PI3K-Akt signaling pathways [46]. Proinflam- cultures of naive Th0 cells and also abrogates the encephalito- matory CXCL10 plays an important role for chemoattraction genic potential of Th9 cells during EAE [54]. of activated T cells to sites of inflammation. CXCL10Ϫ/Ϫ Whereas the nature of IL-27 effects on Th1 cell responses mice display impaired T cell responses, including proliferation (and IFN-␥) may vary in the context of different diseases, after challenge, secretion of IFN-␥, and pathogen there is clear evidence that IL-27 is a suppressor of Th2 and clearance [47]. Th17 cells [11, 38, 49]. IL-27 promotes a population of Tregs Finally, IL-27 promotes protective tumor surveillance against (T-betϩCXCR3ϩ) with distinct transcriptional activation pro- endogenous murine tumors [48]. In settings of mammary car- files compared with Tregs induced by IFN-␥ [55]. In Tr1 cells, cinoma or fibrosarcoma, the development and tumor growth metallothioneins appear to act as natural antagonists of IL-27 in IL-27RAϪ/Ϫ mice were accelerated, and IL-27RAϪ/Ϫ mice [56]. For example, in Tr1 cells from metallothionein-deficient displayed a defective IFN-␥ response and higher frequencies of mice, IL-27 mediated more abundant STAT1/STAT3 phosphory- Tregs [48]. lation, resulting in higher IL-10 production, together with more efficient suppression of effector T cell proliferation [56]. Findings in several other studies have suggested anti-inflam- matory properties of IL-27. IL-27RAϪ/Ϫ mice were highly sus- INHIBITION OF INFLAMMATION BY IL-27 ceptible in the recovery phases following Plasmodium berghei ϩ Several reports have suggested that IL-27 may play a minor infection, and IL-27RAϪ/Ϫ mice developed exuberant CD4 role for clearance of intracellular pathogens during infection Th1 cell-associated liver pathology in an IL-10-resistant manner but may be essential for immune down-modulation during the [57]. IL-27A signaling, during experimental malaria infection, chronic phases of inflammation, which is critical for reduced suppressed the development of killer cell-like receptor group intensity of tissue injury and organ dysfunction. For instance, 1-expressing, terminally differentiated Th1 cells by desensitiz- ϩ IL-27RAϪ/Ϫ mice infected with T. gondii were still capable of ing these cells to the effects of IL-12 and IL-2 [58]. CD4 T developing a protective T cell response and control of parasite cells from expressed higher numbers of the CCR5 re- replication [21]. However, infected IL-27RAϪ/Ϫ mice failed ceptor (ligands: CCL4, CCL5) when genetically deficient of to silence these protective responses, and mice consecutively IL-27RA [59]. This suggests that during malaria, infection ϩ developed a lethal, T cell-mediated inflammation, including IL-27 restricts the chemotactic response of CD4 T cells, al- exuberant IFN-␥ production and T cell proliferation [21]. This though this appears to be contradictory to the findings that is, in part, contradictory to earlier findings of IL-27 synergizing IL-27 can induce CXCL10 (see above) [46]. with IL-12 to induce IFN-␥ from naive CD4ϩ cells [1]. Follow- In collagen-induced arthritis, using a bioengineered EBI3-L- ing protozoan infection with T. cruzi, IL-27RAϪ/Ϫ mice dis- p28-Fc protein ameliorated joint inflammation, histology played prolonged parasitemia, severe liver injury, and in- scores, and release of IL-6, IL-17, and IFN-␥ [36]. TNBS-in- creased mortality compared with WT mice [38]. Splenocytes duced colitis was improved, including suppression of IL-17, from IL-27RAϪ/Ϫ mice secreted enhanced levels of Th2 cyto- following administration of IL-27 [39]. In contrast to kines, as well as enhanced IFN-␥, IL-6, and TNF-␣ production EBI3Ϫ/Ϫ mice [44], conditional CD11c-p28(flox/flox)Ϫ/Ϫ in liver [38]. mice were highly susceptible to Con A-induced liver injury It is well established that IL-27 can act with anti-inflamma- [60]. In keratinocytes and fibroblasts, IL-27 induced the pro- tory function via induction of IL-10 from various T cell sub- duction of anti-inflammatory IL-18-binding protein, a natural sets, including Tregs [49]. IL-27 used the transcription factors antagonist of IL-18 [61]. Finally, transgenic mice, overexpress- STAT1 and STAT3 to induce IL-10 in Th1, Th2, and Th17 ing p28 in T and B cells, were found to suppress IL-6R signal- cells [34]. In another study, IL-27-mediated gene expression of ing by direct interaction of p28 with the gp130R chain [5]. IL-10 in IFN-␥ϩ Foxp3-Th1 cells, via STAT1 and IL-27RAϪ/Ϫ mice, displayed fewer IL-10ϩ T cells after L. monocytogenes in- IMPLICATIONS OF IL-27 DURING HUMAN fection or EAE [37]. Likewise, IL-27 regulated IL-10 produc- ϩ DISEASE tion by CD4 cells following infection with Leishmania major [50]. Mechanistically, IL-27 appears to induce the transcrip- There is accumulating evidence suggesting various roles of tion factor AhR, which partners with c-Maf to transactivate the IL-27 during autoimmune diseases in humans. Elevated con- IL-10 gene promoter region, at least in Tregs (Tr1) [13]. Ad- centrations of IL-27 were found in synovial fluids but not ditional transcription factors involved in IL-27-mediated ex- plasma of patients with rheumatoid arthritis [62]. Gene ex- pression of IL-10 have been identified as Egr-2 and B lympho- pression of p28 and EBI3 was elevated in colonic mucosa of cyte-induced maturation protein-1 [51]. IL-27 failed to induce patients with active Crohn’s disease [63]. In patients with pso- IL-10 in CD4ϩ T cells derived from Egr-2Ϫ/Ϫ mice [51]. The riasis, the serum concentrations of IL-27 were elevated com- loss of gp130 expression on CD8ϩ memory cells was associated pared with healthy controls, correlating with disease severity with limited IL-27 responsiveness and diminished IL-10 pro- and release of IFN-␥ [64]. It has been suggested that endoge- duction during antigen rechallenge [52]. nous release of IL-27 mediates the clinical response following It is worth mentioning that several anti-inflammatory effects therapeutic administration of IFN-␤ in patients with multiple of IL-27 are independent of IL-10, such as IL-27-mediated sup- sclerosis [65]. IL-27 concentrations were also elevated in pa- pression of Th17 cells during EAE [53]. In addition, IL-27 tients with moderate or severe aplastic anemia, correlating blocks the pathway for Th9 cell differentiation when added to with the release of IFN-␥ [66]. SNPs, in the gene encoding for

1162 Journal of Leukocyte Biology Volume 94, December 2013 www.jleukbio.org Bosmann and Ward IL-27 regulates inflammation

IL-27, have been associated with the incidence of several auto- AUTHORSHIP immune diseases, such as asthma [67], chronic obstructive pul- The manuscript was written by M.B. and edited by P.A.W. monary disease [68], and inflammatory bowel diseases [68], all studied in Asian populations. One of these SNPs (g.-964AϾG) is located in the promoter region of p28 and may influence the ACKNOWLEDGMENTS binding affinity of a yet-to-be-identified [67]. IL-27 has been evaluated recently as a novel, diagnostic bio- This study was supported by grants from the U.S. National In- marker for bacterial infections [69], whereas production of stitutes of Health (GM-29507 and GM-61656 to P.A.W.), the IL-27 appears to be suppressed during HIV infection [70]. Deutsche Forschungsgemeinschaft (BO 3482/3-1 to M.B.), the However, a functional IL-27 response would likely be helpful Federal Ministry of Education and Research (BMBF; to control HIV replication [71]. IL-27 was found recently to 01EO1003 to M.B.), the B. Braun Foundation (to M.B.), the confer resistance of macrophages to HIV by inhibiting spectrin Mainzer Forschungsförderungsprogramm (MAIFOR Program) ␤ nonerythrocyte 1, a required host factor for HIV-1 infection of the University Medical Center Mainz (to M.B.), and a Marie [72]. Furthermore, IL-27 induced the expression of novel Curie Career Integration grant of the European Union (Proj- microRNAs (miR-SX1, -SX2, -SX3, and -SX6) in human macro- ect 334486 to M.B.). phages, which antivirally target the open reading frames of a number of viruses (HSV-1, HSV-2, and HHV-8) [73]. On the other hand, whereas infections with hepatitis B virus mediate DISCLOSURES The authors are responsible for the contents of this publication. The authors the release of IL-27 [74], quantification of IL-27 may not be have no commercial or financial conflicts of interests. useful in determining pathologic stages and progression of liver disease [75]. 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